Chronic pain due to various health conditions is a common clinical problem in patients. Currently, opioid-based analgesics remain the most effective pain reliever and have been increasingly used for pain control in recent years. However, repeated use of opioids causes aversive side effects, including those causing opioid misuse and addiction due to strong rewarding properties of opioids. In fact, as medical use of opioids is increased, so is misuse of prescription opioids and opioid addiction. Concerns over non-medical misuse of opioids and risk of developing opioid addiction have significantly limited optimal use of opioid therapies in non-malignant pain patients. Nevertheless, there are few preclinical or clinical studies concerning the effects of repeated opioids for pain control on the risk of developing compulsive behaviors of opioid misuse and addition. One of the key issues in question is how repeated opioid treatment for pain control alters individual's response or sensitivity to opioid's rewarding effect, the pharmacological driving force for compulsive behaviors in opioid misuse and addiction. Recent studies including ours have shown that prolonged opioid exposure and chronic pain both induce new functional delta-opioid receptors (DOR) in pain-modulating brain areas, leading to enhanced opioid analgesia. However, the role of DOR in opioid reward is largely unknown at present. In our pilot study in animal models, we have found that prior exposure to repeated opioids increases the sensitivity to the rewarding effect of subsequent opioids. This intriguing and provoking finding prompted us to explore this important issue in this R21 proposal. Based on our preliminary findings, this research proposes two specific aims to focus on two foremost issues: 1) how do presence of pain and repeated opioid exposure affect reward sensitivity to subsequent opioids? And 2) does DOR play a critical role in the changed reward sensitivity? Aim 1 studies will use rat models of persistent pain and behavioral measures of opioid reward to determine whether pain exacerbates repeated opioid-induced increase in reward sensitivity. Aim 2 studies will determine whether new functional DOR is recruited by repeated opioids and by persistent pain in a reward-related brain area, resulting in DOR-mediated increase in reward sensitivity. Combining synaptic analysis and behavioral measures, these proposed studies may identify a novel function of DOR in the adaptive properties of brain's reward function and provide a fundamental platform for future studies on the cellular and molecular mechanisms underlying DOR-mediated changes in reward sensitivity. Understanding the impact of chronic pain and prior opioid exposure on the rewarding property of opioids will provide insights necessary for the development of improved opioid therapies that produce optimal pain control while minimizing the risk of opioid misuse and addiction. PUBLIC HEALTH RELEVANCE: Repeated use of opioid analgesics for control of chronic pain has the potential to cause compulsive behaviors of opioid misuse and addiction due to the strong rewarding effect of opioids. This research proposal investigates how the presence of pain and repeated opioid treatment may change individual response and sensitivity to the rewarding effect of subsequent opioids, the pharmacological driving force for the compulsive behaviors. Information obtained from these studies will provide necessary insight for the development of effective opioid therapies that provide optimal pain control while minimizing opioid misuse and addiction.